JP2008522150A - Means and methods for reducing magnetic crosstalk in biosensors - Google Patents

Abstract

A magnetic sensor MS that detects a leakage magnetic field SF generated by a magnetizable object SPB when magnetized and generates an electric object signal U _OB that depends on the detected leakage magnetic field SF, the sensor comprising: An electric object caused by magnetic crosstalk between the magnetic field generators WR ₁ and WR ₂ for generating a main magnetic field H for magnetizing the magnetizable object SPB and the main magnetic field H and the leakage magnetic field SF and a crosstalk reducing unit for reducing the influence of crosstalk signal component in the signal U _OB, the crosstalk reduction unit, with the rest of said cross-talk signal component the electrical object signal U _OB sensor configured to distinguish signal characteristics between, and generates an electrical output signal U _O. The signal characteristic may be, for example, a signal phase. In this case, the cross-talk reduction means multiplies the means PHSFT for generating an orthogonal electric signal U _ORT perpendicular to the cross-talk signal component, the quadrature electrical signals U _ORT by the electrical object signal U _OB And the resulting signal U _MP after the multiplication may form a reference for the electrical output signal U _O. The frequency ω ₁ of the main magnetic fields H and H ₁ is preferably such that the phase difference expressed in radians between the detected leakage magnetic field SF and the main magnetic fields H and H ₁ is substantially equal to π / 2 + nπ. Where n is an integer. The signal characteristic may be, for example, a signal amplitude. In this case, the main magnetic field H is first frequency _{f 1,} a first magnetic signal _{H 1} with omega _1, wherein the first frequency _{f 1,} fairly long and the magnetizable objects SPB than omega ₁ magnetization cut-off frequency _{f c} a second frequency _{f 2} greater than, omega ₂ second and a magnetic signal _{H 2} having a magnetic signal _H 1 of the first and second 2, _{H 2} of the Generating a first electrical signal component in the electrical object signal U _OB having a first frequency f ₁ and a first amplitude, and in the electrical object signal having a second frequency f ₂ and a second amplitude; A second electrical signal component is generated. The crosstalk reducing means includes means G _V , MP ₁ , MP ₂ , and DFF for measuring the amplitudes of the first and second electric signal components and subtracting the measured amplitudes from each other. The latter resulting signal forms the reference for the electrical output signal U _O. In either case, the crosstalk reducing means may comprise a low pass filter LPF for filtering the resulting signal after the subtraction, the resulting signal after the low pass filter LPF being the electrical output. The signal U _O may be used.

Description

  The present invention relates to a method for detecting a leakage magnetic field generated by a magnetizable object when magnetized.

  The invention further relates to a magnetic sensor for performing said detection and the use of such a sensor in a biochip for eg molecular diagnostics, biological sample analysis or chemical sample analysis.

  The introduction of microarrays or biochips has revolutionized the analysis of samples for DNA (desoxyribonucleic acid), RNA (ribonucleic acid), nucleic acids, proteins, cells and cell debris, tissue components, and the like. Its applications are, for example, human genotyping (eg in hospitals or by individual doctors or nurses), medical screening, biological and pharmacological research, detection of drugs in saliva, etc. The purpose of a biochip is to detect and quantify the presence of biomolecules in a sample (usually a solution).

  A biochip (also referred to as a biosensor, biosensor chip, biomicrochip, gene chip or DNA chip) is, in its simplest form, from a substrate to which a large amount of various probe molecules are attached in a specific region of the biochip. Become. If they match, the molecule or molecular fragment to be analyzed can be bound to the substrate.

The term “substrate” includes any underlying material that can be utilized on which an element, circuit, or epitaxial layer may be formed. The term “substrate” also refers to a semiconductor substrate such as a doped silicon, gallium arsenide (GaAs), gallium arsenide phosphorus (GaAsP), indium phosphide (InP), germanium (Ge) or silicon germanium (SiGe) substrate. May also be included. A “substrate” can include, for example, an insulating layer such as a SiO ₂ or Si ₃ N ₄ layer in addition to a semiconductor substrate portion. Thus, the term “substrate” also includes glass, plastic, ceramic, silicon-on-glass, silicon-on-sapphire substrates. The term “substrate” is thus used to define generally the elements for the layer underneath the layer or portion of interest. The “substrate” may also be any other foundation on which a layer such as a glass or metal layer is formed.

  For example, a fragment of a DNA molecule binds to one unique piece of complementary DNA (c-DNA) molecule. The appearance of the binding reaction is detected, for example, by using a fluorescent marker that binds to the molecule to be analyzed. As an alternative to fluorescent markers, magnetizable objects can be used as magnetic markers coupled to the molecules to be analyzed. What the present invention deals with is the latter type of marker. In a biochip, the magnetizable object is usually mounted with so-called superparamagnetic beads. This provides the ability to analyze small amounts of many different molecules or molecular fragments simultaneously in a short time. One biochip can perform analysis on 10 to 1000 or more different molecular pieces. As a result of projects such as the Human Genome Project and follow-up studies on gene and protein function, the usefulness of information that may be made available through the use of biochips is expected to increase rapidly over the next decade. A general description of the function of the biochip has already been described in International Patent Application Publication WO03 / 054523A2.

  A biochip consisting of an array of sensors (eg 100) based on the detection of superparamagnetic beads is a lot of different molecules (eg proteins, DNA, drugs of abuse, hormones) in a sample solution (eg a solution like blood or saliva) Can be used to measure the concentration of The sample solution has a target molecular species or antigen. Any biomolecule that can carry a magnetic label (marker) has applicability. The measurement involves attaching a paramagnetic bead to the target, magnetizing the bead using an applied magnetic field, and (for example) a stray field of the magnetized bead using a giant magnetoresistive (GMR) sensor. Can be realized by detecting.

  The present application focuses on biochips based on excitation of superparamagnetic nanoparticles. However, use in other magnetoresistive sensors such as anisotropic magnetoresistance (AMR) and tunneling magnetoresistance (TMR) is also part of the present invention. The magnetic field generator may have a current flowing through a line that generates a magnetic field, thereby magnetizing the superparamagnetic beads. The leakage magnetic field from the superparamagnetic beads generates an in-plane magnetization component in the GMR, resulting in a change in resistance.

  For further explanation of the background of the invention, reference is made to FIGS.

FIG. 2 shows an example of the magnetic sensor MS on the substrate SBSTR. Single or multiple such sensors may be integrated on the same substrate SBSTR to form a biochip BCP as schematically shown in FIG. The magnetic sensor MS is in this embodiment integrated in the substrate SBSTR by the first conductive line WR ₁ example, with a magnetic field generator. Magnetic sensor also includes a second (or more) conductive lines WR ₂ may have. In order to generate the magnetic field H, other means may be used instead of the conductive wire. The magnetic field generator may also be placed outside the substrate SBSTR (external excitation). In each magnetic sensor MS, a magnetoresistive element, for example a giant magnetoresistive GMR, is integrated into the substrate SBSTR, thereby reading out the information collected by the biochip BCP and thus via the magnetizable object of the target molecule TR. Read the presence or absence, thereby determining or estimating the surface density of the target molecule TR. The magnetizable object is preferably realized by so-called superparamagnetic beads SPB. A binding site BS capable of selectively binding the target TR is mounted on the probe element PE. The probe element PE is attached to the upper end of the substrate SBSTR.

The functions of the magnetic sensor MS or more generally the biochip BCP are as follows. Each probe element PE is provided with a specific type of binding site BS. If the target sample TR is presented to the probe element PE or passes over the probe element PE and the binding site BS and the target sample TR match, they bind to each other. Superparamagnetic beads SPB bind directly or indirectly to the target sample TR. Superparamagnetic beads SPB make it possible to read the information collected by the biochip BCP. Superparamagnetic particles have zero time-averaged magnetization with zero applied magnetic field due to frequent thermally induced magnetic moment reversals on the time scale of magnetization measurement (polymer ) Suspend in binder or substrate. The average inversion frequency is
ν = ν ₀ exp (−KV / kT)
Given by. Where KV (K is the magnetic anisotropy energy density and V is the particle volume) is an energy barrier that needs to be overcome, ν ₀ is the frequency of inversion trials (typically 10 ⁹ s ⁻¹ ), and k is Boltzmann Constant, T is absolute temperature (Kelvin).

The magnetic field H magnetizes the superparamagnetic beads SPB, and the superparamagnetic beads SPB in response generates a leakage magnetic field SF that can be detected by the GMR. Although not required, the GMR should preferably be arranged such that a portion of the magnetic field H passing through the GMR is perpendicular to the sensitive direction of the GMR layer. GMR is (not words GMR inside) outside the whole is sensitive magnetic field is indicated by _{H ext} in FIG.

Assuming that the biochip BCP is placed horizontally (and thus perpendicular to gravity), the GMR is placed only in a magnetic field with a horizontal component or mainly sensitive to a magnetic field with a horizontal component. . This minimizes the sensitivity of the GMR to the magnetic field H and thus minimizes the magnetic crosstalk between the magnetic field H and the GMR. If the magnetic field H passes through the GMR completely perpendicular to the GMR, the magnetic field H has no horizontal component. On the other hand, the leakage magnetic field SF has a horizontal component and causes a difference in the resistance value of the GMR. This allows an electrical output signal (generated by a current change passing through the GMR when biased by a DC voltage not shown in FIG. 1, for example) to be output by the sensor MS, and the target TR A measure of the amount of In practice, however, the GMR cannot be made infinitely small (in the vertical direction). Therefore, the horizontal component of the magnetic field H is always available (for example, when the applied magnetic field lines are not perfectly uniform, such as a circular object magnetic field generated by an integrated current). Furthermore, GMR is not completely sensitive in only one direction. Furthermore, the alignment of the magnetic field H with the GMR is not perfect and can even be undesirable for some mechanistic positional reasons. All of these imperfections lead to a constant crosstalk between the magnetic field and the GMR, ie the detected output signal does not depend only on the leakage field SF, but also directly on the magnetic field H. It becomes. The crosstalk is shown as H _X in FIG. Crosstalk reduces the accuracy of measuring the density of large numbers of different biomolecules. The accuracy of the measurement can be too bad, especially if the leakage field SF is very weak (or the magnetic crosstalk field is not stable) and therefore a very high sensitivity of the magnetic sensor MS is required. For very sensitive measurements, the magnetic crosstalk can even be 10 times higher than the leakage field SF. This, of course, makes the measurement useless. Therefore, there is a high need to reduce magnetic crosstalk or reduce the effects of magnetic crosstalk.

  Therefore, an object of the present invention is to provide a magnetic sensor for detecting a leakage magnetic field generated by a magnetizable object when magnetized, producing an output signal that is substantially dependent only on the detected leakage magnetic field. There is to do.

  To achieve this object, the present invention is a magnetic sensor for detecting a leakage magnetic field generated by a magnetizable object when magnetized and generating an electric object signal dependent on the detected leakage magnetic field. The sensor includes a magnetic field generator for generating a main magnetic field for magnetizing the magnetizable object, and in the electric object signal caused by magnetic crosstalk between the main magnetic field and the leakage magnetic field. Crosstalk reducing means for reducing the influence of the crosstalk signal component, the crosstalk reducing means distinguishing signal characteristics between the crosstalk signal component and the rest of the electrical object signal. A sensor configured to generate an electrical output signal is provided.

  By distinguishing the signal characteristics between the crosstalk signal component and the rest of the electrical object signal, the crosstalk can be separated from the object signal, thus producing an output signal without crosstalk. it can.

  The signal characteristic may be, for example, a signal phase. The distinction between magnetic crosstalk (ie magnetic field coming directly from a magnetic field generator) and leakage magnetic field (ie magnetic field coming from a magnetic field generator via a paramagnetic bead) is that the leakage magnetic field is compared to the (direct) magnetic field. This is possible due to the fact that it is delayed in time. The crosstalk reducing means may comprise means for generating an orthogonal electrical signal orthogonal to the crosstalk signal component, and a multiplier for multiplying the orthogonal electrical signal by the electrical object signal, The resulting signal after the multiplication may form a reference for the electrical output signal. The resulting signal may be used directly as an electrical output signal. Preferably, however, the crosstalk reducing means comprises a low pass filter that filters the resulting signal after the multiplication. At this time, the low-pass filter generates an electrical output signal. The frequency of the main magnetic field may be selected such that the phase difference expressed in radians between the detected leakage magnetic field and the main magnetic field is approximately equal to π / 2 + nπ, where n is It is an integer. In this way, the sensor gain is maximized.

  Another signal characteristic may be, for example, the amplitude of the signal. For example, this means that the main magnetic field has a first magnetic signal having a first frequency and a second frequency that is much longer than the first frequency and longer than the magnetization cutoff frequency of the magnetizable object. And a second magnetic signal having. For frequencies higher than the magnetization cutoff frequency, the strength of the generated stray field decreases with increasing frequency. The first and second magnetic signals generate a first electrical signal component in the electrical object signal having the first frequency and a first amplitude, and have the second frequency and the second amplitude. A second electric signal component in the electric object signal is generated. The crosstalk reducing means has means for measuring the amplitudes of the first and second electric signal components and subtracting the measured amplitudes from each other, and the resulting signal after the subtraction is the electric signal. Form a reference for the output signal. The resulting signal may be used directly as an electrical output signal. Preferably, however, the crosstalk reducing means comprises a low pass filter for filtering the resulting signal after the subtraction. At this time, the low-pass filter generates an electrical output signal. Preferably, the first frequency is lower than the magnetization cutoff frequency and the second frequency is much higher than the magnetization cutoff frequency. In this way, both the magnetic crosstalk and the leakage magnetic field are hardly attenuated in the GMR at the first frequency, while the magnetic crosstalk is hardly attenuated and the leakage magnetic field is dramatically reduced at the second frequency. It is done. This makes crosstalk cancellation very easy. This is because at this time both the resulting object signals, each having the first and second frequencies, need only be subtracted from each other, and it is not necessary to adapt the amplitude of at least one of the object signals. .

  In the above-described embodiment of the present invention, the effect of magnetic crosstalk is reduced. However, it is also possible to erase the magnetic crosstalk more directly. Therefore, the present invention also provides a magnetic sensor that detects a leakage magnetic field generated by a magnetizable object when magnetized and generates an electrical object signal that depends on the detected leakage magnetic field, the sensor comprising: Caused by a first external magnetic field generator for generating a first main magnetic field for magnetizing the magnetizable object, and magnetic crosstalk between the first external main magnetic field and the leakage magnetic field Crosstalk reducing means for reducing the influence of the crosstalk signal component in the electrical object signal, wherein the crosstalk reducing means is a magnetic field between the first external main magnetic field and the leakage magnetic field. A sensor is provided having a second external magnetic field generator for generating a second main magnetic field for compensating for crosstalk. By selecting appropriate values for the amplitude and phase of the second main magnetic field, magnetic crosstalk is eliminated. The first and second external magnetic field generators may have, for example, first and second coils through which first and second alternating currents flow, respectively, where the first and second alternating currents are provided. Have the same frequency and flow during operation of the magnetic sensor. The crosstalk reducing means may include means for adapting a ratio between the amplitude of the first alternating current and the amplitude of the second alternating current in order to minimize the magnetic crosstalk. The crosstalk reducing means may further comprise means for adapting a difference between the phase of the first alternating current and the phase of the second alternating current in order to further reduce the magnetic crosstalk. This is a simple way to adapt the mutual strength and phase of the first and second magnetic fields. This is because no mechanical adaptation is required. The adaptation can be performed automatically, for example by applying generally known feedback techniques.

The present invention is further a method for detecting a leakage magnetic field generated by a magnetizable object when magnetized, comprising:
In the first main step,
Generating a main magnetic field in the absence of a magnetizable object;
Detecting the magnetic field as if it were a stray field generated from the magnetizable object if there was a magnetizable object;
Generating an electrical object signal from the detected magnetic field;
Measuring the amplitude of the electrical object signal;
Storing the amplitude of the electrical object signal in a memory; and
In the second main step,
Generating a main magnetic field for magnetizing the magnetizable object;
Detecting a leakage magnetic field generated from the magnetizable object;
Generating a further electrical object signal from the detected leakage magnetic field;
Measuring the amplitude of the further electrical object signal;
Obtaining an amplitude of the stored electrical object signal;
Subtracting the stored amplitude and the amplitude of the further electrical object signal from each other, thereby generating an electrical output signal;
A step of performing
A method is provided.

  The advantage of the present method over the above-described method of reducing magnetic crosstalk is the fact that no functional changes are required in the sensor. Thus, the method can be successfully applied not only to the biochip of the present invention disclosed herein, but also to prior art biochips.

  The invention will be further described with reference to the accompanying drawings.

  The figures are merely schematic and are not limiting. In the drawings, the size of some of the elements are exaggerated and not drawn on scale and are for illustrative purposes only. The description with respect to the drawings is merely illustrative of the principles of the invention and should not be construed as limiting the invention to the description and / or drawings.

FIG. 3 shows the resistance of the GMR as a function of the magnetic field component H _ext . Note that the sensitivity of _GMR s _GMR = dR _GMR / dH _ext is not constant but depends on H _ext .

  In a sensor MS as shown in FIG. 2, instead of a giant magnetoresistance GMR, it depends on a magnetic field, such as a specific type of resistance such as tunneling magnetoresistance (TMR) or anisotropic magnetoresistance (AMR). Any other means having characteristics (parameters) may be used. In AMR, GMR, or TMR materials, the electrical resistance changes when the magnetization direction of one or more layers changes as a result of the application of a magnetic field. GMR is a magnetoresistance for a layer structure having a conductive intermediate layer between so-called switching magnetic layers, and TMR is a magnetoresistance for a layer structure having a magnetic metal electrode layer and a dielectric intermediate layer.

  In GMR technology, structures have been developed in which two very thin magnetic films are very close together. The first magnetic film is usually fixed by holding the first magnetic film close to the exchange bias layer, which means that the magnetization direction of the first magnetic film is fixed. The exchange bias layer is a layer of an antiferromagnetic material that fixes the magnetization direction of the first magnetic film. The second magnetic layer or free layer has a freely variable magnetization direction. In this example, the change in the magnetic field due to the change in magnetization of the superparamagnetic particles SPB causes the free magnetic layer to rotate in the magnetization direction, and then causes the resistance of the GMR structure to increase or decrease. Low resistance generally occurs when the sensor and the fixed layer are magnetically oriented in the same direction. High resistance occurs when the magnetic orientation of the sensor and the fixed layer (film) is opposite to each other.

  The TMR consists of two ferromagnetic electrode layers separated by an isolation (tunnel) barrier. The barrier needs to be very thin, i.e. on the order of 1 nm. Only then can electrons tunnel through the barrier. This is a quantum mechanical transport process. By utilizing an exchange bias layer, the magnetic alignment of one layer can be changed without affecting the other. In this example, the change in the magnetic field due to the change in the magnetization of the superparamagnetic particle SPB causes the sensor film to rotate in the magnetization direction, and then increases or decreases the resistance of the TMR structure.

  In AMR, the resistance of a ferromagnetic material depends on the angle that the current makes with the direction of magnetization. This phenomenon is due to asymmetry in the electron scattering cross section of the ferromagnetic material.

4, in order to distinguish between the remaining crosstalk signal components and the object signal in the object signal U _OB, the phase difference between the leakage magnetic field SF sensed crosstalk signal is used, the embodiment of the present invention Show. The magnetic sensor MS has a generator G for generating an AC (alternating current) voltage / current having an angular frequency ω ₁ . The generator generates an AC current flowing through the line WR ₁ and generates the main magnetic field H accordingly (see FIG. 2). The main magnetic field H magnetizes the superparamagnetic beads SPB and generates a leakage magnetic field SF accordingly (see also FIG. 2). As described above with reference to FIGS. 1 and 2, since the leakage magnetic field SF has a large component in the sensitive (x) direction of the GMR, the GMR can detect the leakage magnetic field SF (in FIG. 2). see x direction). As explained earlier, there is always some horizontal component of the magnetic field detected in the GMR that is directly attributable to the main magnetic field H (ie not via the paramagnetic beads SPB). This so-called magnetic crosstalk is shown as _{HXT in} FIG. GMR is biased by a current _{i s} output by DC current source _{I BIAS.} Current _{i s} generates an internal magnetic field in the GMR. Therefore, by selecting an appropriate value of the current i _s, the curve shown in Figure 3 can be allowed to "move" in the horizontal direction, it is possible to correct the sensitivity of the GMR is selected. In most cases, the highest sensitivity possible (“highest” negative slope in FIG. 3) will be selected. The magnetic sensor MS further includes an amplifier AMP, a phase shifter PHSFT, a multiplier MP, and a frequency low-pass filter LPF. The input of the amplifier AMP is coupled to the GMR for receiving voltage changes caused by the leakage magnetic field SF. The voltage change is buffered and preferably amplified by an amplifier AMP. Amplifier AMP, at the output of the amplifier AMP, outputs the object signal _{U OB.} The input of the phase shifter PHSFT is coupled to receive an AC signal that is in phase with the AC current flowing through line WR ₁ , and thus both the main magnetic field H and the crosstalk field H _XT are also in phase. Phase shifter PHSFT outputs a quadrature electrical signals _{U ORT} 90 degrees out of phase with the AC signal is delayed at the input of the該移phase shifter PHSFT. The magnetic crosstalk H _XT is represented by the following equation [1]:
H _XT = H ₁ cos ω ₁ t [1]

The magnetic field component of the magnetized paramagnetic bead SPB, which is observed by the magnetic sensor MS, is delayed by a phase amount φ with _respect to the crosstalk field _HXT . Therefore, the leakage magnetic field SF is represented by the following formula [2]:
SF = H _b cos (ω ₁ t−φ) [2]
_Hb depends on the number of beads.

The effect of the delay is modeled by magnetization and relaxation time constants. The relaxation time constant τ _neel represents the relaxation time when the excitation field decreases to zero (“Neel relaxation” by R. Koetiz et al. (“Journal of Magnetism and Magnetic Materials”, 194 (1999), p. 62)). reference). Due to the time taken to magnetize the paramagnetic beads SPB, the leakage magnetic field SF of the paramagnetic beads SPB is delayed from the applied main magnetic field H. This is in contrast to a crosstalk field _HXT having a phase that is substantially the same as the phase of the main magnetic field H. At the angular frequency ω << 1 / _τneel , the phase delay φ is small. However, the phase of the crosstalk field _HXT , which is essentially a component of the main magnetic field H applied, does not change. This still results in the phase difference between the magnetic crosstalk field H _XT and the leakage field SF from the paramagnetic beads SPB in the magnetic sensor MS. After amplification by the amplifier AMP, the object signal U _OB is demodulated using the quadrature electrical signal U _ORT = sinω ₁ t. The demodulation is performed by a multiplier MP that multiplies the object signal U _OB by the quadrature electrical signal U _ORT, thereby providing a measure of the amount of target particles TR (see FIG. 2) at the output of the multiplier MP. Output a signal U _MP without crosstalk, which forms the reference for the electrical output signal U ₀ . The object signal U _OB is represented by the following equation [3]:
_{U OB αH b cos (ω 1} t-φ) · sinω 1 t = 1/2 · H b {sinφ + sin (2ω 1 t-φ)} [3]

After the low pass filter LPF, the output signal U ₀ is represented by the following equation [4]:
U ₀ = 1/2 · H _b sinφ [4]

From equation [4], it is clear that the output signal U ₀ represents the number of paramagnetic beads SPB near the magnetic sensor MS and does not represent magnetic crosstalk H _XT . This is because only the amplitude H _b (see Equation [2]) exists in Equation [4], and there is no amplitude H ₁ (see Equation [1]). From equation [4], in order to reach the maximum gain in the magnetic sensor MS is the phase delay sine (= sin [phi) is should be equal to 1, thus vibration frequency omega ₁ of the main magnetic field H is preferably square It is clear that the phase delay φ expressed in frequency should be selected to be approximately equal to π / 2 + nπ (n is an integer). Obviously, the phase shift in PHSFT is corrected for the delay or phase shift in the amplifier.

FIG. 6 shows an implementation of the invention in which the amplitude difference between the crosstalk signal H _XT and the detected leakage field SF is used to distinguish the crosstalk signal component in the object signal U _OB from the rest of the object signal. An example is shown. Similar to the embodiment described above, the magnetic sensor MS comprises an AC generator G (in this example the AC generator generates a first frequency f ₁ and a second frequency f ₂ ), lines WR ₁ , GMR, DC It has a current source I _BIAS , an amplifier AMP, and a frequency low-pass filter LPF. The magnetic sensor MS further includes addition means SM, a gain adaptor G _V , a first multiplier MP ₁ , a second multiplier MP ₂ and a subtractor DFF. First first input of the input unit and the multiplier MP ₂ of the multiplier MP ₁ is coupled to the output of the amplifier AMP. A second input of the first multiplier MP ₁ is to receive an AC signal having a first frequency f _1, it is coupled via a gain adaptation unit G _V. A second input of the second multiplier MP ₂ is coupled to receive an AC signal having a second frequency f _2. The subtractor DFF is coupled with the output of the first multiplier MP ₁ by means of a first input, in particular for receiving the _first DC signal DC ₁ , and more particularly for receiving the second DC signal DC ₂ . Therefore, coupled with the second output of the multiplier MP ₂ by the second input unit. The output of the subtractor DFF is coupled to the input of the low pass filter LPF to output the resulting signal after subtraction. The output of the low pass filter LPF, and outputs an output signal _{U 0.} Summing means SM adds the two AC signals from generator G and supplies an AC current flowing through line WR ₁ having both _first and _second frequencies f ₁ and f ₂ (with equal amplitude). To do.

Gain adaptive generator G _V may alternatively generator G and may be disposed between the second second input of the multiplier MP _2. Position of another alternative of the gain adaptive unit G _V is between the first input of the output unit and the first multiplier MP ₁ of the amplifier AMP, the output unit and the second amplifier AMP multiplier MP ₂ Between the first input section, between the output section of the _first multiplier MP1 and the first input section of the subtractor DFF, and between the output section of the _second multiplier MP2 and the subtractor DFF. Between the two input units.

  FIG. 5 shows a Bode diagram for further explaining the embodiment of the present invention shown in FIG.

The functions of this embodiment are as follows. The applied main magnetic field H (see FIG. 2) consists of two frequencies, a relatively low frequency f ₁ and a relatively high frequency f ₂ . Since the magnetic crosstalk H _XT is frequency independent, the resulting crosstalk signal amplitude is equal for both frequencies. Accordingly, the crosstalk signal H _XT is represented by the following equation [5]:
H _XT = H ₁ cos ω ₁ t + H ₂ cos ω ₂ t [5]

However, the signal from the paramagnetic beads SPB depends on the frequency. When the frequency f _{1 of the} applied magnetic field H ₁ is much higher than the magnetization cutoff frequency (ω _c = 1 / τ _Neel ) of the beads, the paramagnetic beads SPB are not easily magnetized, that is, the paramagnetic beads SPB. too "late" to follow the main magnetic field H ₁ that is applied, the signal to be detected is much smaller.

f ₁ <In case _{f c} and _f 2 >> _{f c} is such extreme and preferred, the signal at _{f 1} amplitude includes both a signal from crosstalk and paramagnetic beads SPB, while the amplitude of the signal at f ₂ is only crosstalk. This is because the leakage magnetic field SF is effectively reduced to zero at f ₂ as can be inferred from the Bode diagram of FIG. In the latter case, the leakage magnetic field SF is expressed by Equation [2].

The parallel demodulation of the material signal U _OB , _one using the _first multiplier MP ₁ with the first frequency f ₁ and the other using the second multiplier MP ₂ with the second frequency f ₂ , Among other things, each results in a _first DC signal DC ₁ and a second DC signal DC ₂ . Basically, the first DC signal DC ₁ is represented by the following equation [6]:
DC ₁ = H ₁ + H _b [6]
The second DC signal DC ₂ is represented by the following formula [7]:
DC ₂ = H ₂ [7]

Assuming H ₁ = H ₂ , the resulting DC component in the resulting signal output by the subtractor DFF has only the value H _b . Preferably, the resulting signal is filtered by a low pass filter LPF to output a pure DC signal U ₀ with value H _b . Ideally, the adaptive unit G _V is not essential (in other words, may have a gain value equal to 1). However, if the value H ₁ is not equal to the value H ₂ , the signal U ₀ is still determined solely by the value H _b if the gain adaptor G _V is present and outputs an appropriate gain correction factor. Thus, for example, it is possible even when the second frequency f ₂ is not f ₂ >> f ₁ but simply f ₂ > f ₁ . Although not preferred, the present invention still operates even when the first and second frequencies f ₁ and f ₂ are both higher than the so-called cutoff frequency. In any _case, a _f 2> f _c.

FIG. 7 shows an embodiment of the present invention in which an additional magnetic field is generated to compensate for the magnetic crosstalk field. In the above-described embodiment of the present invention, the effect of magnetic crosstalk is reduced. However, it is also possible to erase the magnetic crosstalk more directly. Thus, a first external magnetic field generator which is implemented by the first coil L _A for generating a first main field H _A for magnetizing the magnetizable object SPB, a first external magnetic field H _A Crosstalk reducing means for reducing crosstalk signal components in the electrical object signal caused by magnetic crosstalk with the leakage magnetic field SF (not shown in FIG. 7, but see FIG. 2) Provided. Crosstalk reduction means is implemented by the second coil L _B to generate a second main magnetic field H _B for compensating the magnetic cross-talk between the first outer main magnetic field H _A and the leakage magnetic field SF A second external magnetic field generator;

The method of using the interference field H _A and H _B having the same phase and frequency to offset the x-direction component, in order to magnetize the paramagnetic beads SPB (similarly to the above embodiment) internally It can be used for a sensor that utilizes an applied magnetic field or for a sensor that utilizes an externally applied magnetic field to magnetize the paramagnetic beads SPB as shown in FIG. In the latter case, the second coil L _B is the magnetic cross talk due to slight misalignment of the first coil L _A first not completely uniform the applied against the main magnetic field H _A, or, for example, the present invention Other embodiments are used to offset magnetic crosstalk due to any other reason that causes crosstalk for the reasons described above. In Figure 7, for example, the first coil L _A, which is used to magnetize the paramagnetic beads SPB, the magnetic field H _A of the coil occurs is inconsistent to have a small component in the x-direction. In FIG. 7, the misalignment is indicated by an angle α that is not equal to zero. Each during operation of the magnetic sensor MS, the first and second AC current having the same frequency flows through the first and second coil L _A and L _B. By utilizing the second coil L _B to generate a second main magnetic field H _B of and backward have the same amplitude of the x component, that (a crosstalk) x component is canceled it can. The resulting magnetic field H _res thus has no x component, i.e. the magnetic crosstalk is canceled out and in the GMR there is only a horizontal (externally induced) magnetic field in the x direction caused by the leakage magnetic field SF. . Perhaps crosstalk cancellation may be performed automatically, for example by using a generally known feedback technique.

8, prior to the actual (biological) measurements, when the paramagnetic beads SPB does not yet exist, the amplitude of the object signal U _OB is measured and stored during the actual measurement, when the paramagnetic beads are present Shows the method of the present invention in which the stored amplitude is subtracted from the amplitude of the current object signal U _OF , thereby outputting an output signal without crosstalk.

During the first main step, the magnetic sensor MS generates the main magnetic field H in the absence of magnetizable objects, for example in the absence of paramagnetic beads. The magnetic field H is then detected as if there were paramagnetic beads and the magnetic field was due to the paramagnetic beads. Thus, the electric object signal _UOB is generated in the absence of paramagnetic beads. This means that the object signal U _OB is basically 100% magnetic crosstalk. The electrical object signal U _OB is filtered by a frequency low-pass LPF. The output signal _{U 0} results a pure DC signal. The signal is stored in the memory MM.

During the second main step, the magnetic sensor MS generates the main magnetic field H while the paramagnetic beads SPB are present. The magnetic field H is then detected and a further electrical object signal U _FOB is generated. Due to the fact that here the paramagnetic beads SPB are present, the further electrical object signal U _FOB contains the leakage magnetic field SF (and thus contains information on the amount of the target TR (see FIG. 2)) and the magnetic field. It is determined both by crosstalk. The further electrical object signal U _OB is also filtered by a frequency low pass LPF. The resulting further output signal U _0F is also a pure DC signal. The DC signal stored during the first main step is then subtracted from the DC signal generated here by the subtractor SBTR, so that it is a DC signal without crosstalk representing the number of target TRs. A DC output voltage signal U _OUT is generated. This is due to the equal crosstalk component in both signals U ₀ and U _OF . Of course, the subtraction may be reversed. It is also possible to store the signal U _0F and then later obtain both signals U ₀ and U _0F and subtract them from each other to produce the DC output voltage U _OUT .

  The embodiments described above are intended to illustrate rather than limit the invention, and those skilled in the art can design many alternative embodiments without departing from the scope of the invention as defined by the appended claims. It should be noted that it may be possible. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. The word “comprising” does not exclude the presence of elements or steps other than those listed in a claim or in the entire specification. Reference to an element in the singular does not exclude the presence of more than one such element. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used. Any words such as top, bottom, over, under, etc. in the description and in the claims are used for descriptive purposes and are not necessarily relative. It does not indicate the correct position. The terms used in this manner are interchangeable in the appropriate environment, and the embodiments of the invention described herein can operate in different directions than those described or illustrated by the figures. It should be understood that.

1 shows a biochip having a substrate and a plurality of magnetic sensors. An example of a magnetic sensor using integrated magnetic field excitation is shown. The GMR resistance is shown as a function of the magnetic field component in a direction in which the GMR layer is sensitive to the magnetic field. In order to distinguish between the crosstalk signal component in the object signal and the rest of the object signal, an embodiment of the present invention is shown in which the phase difference between the crosstalk signal and the detected leakage magnetic field is utilized. FIG. 7 shows a Bode diagram for further explaining the embodiment of the present invention shown in FIG. 6. In order to distinguish the crosstalk signal component in the object signal from the rest of the object signal, an embodiment of the present invention is shown in which the amplitude difference between the crosstalk signal and the detected leakage magnetic field is utilized. Fig. 4 shows an embodiment of the invention in which an additional magnetic field is generated to compensate for the magnetic crosstalk field. Before the actual (biological) measurement, the amplitude of the object signal is measured and stored when the paramagnetic beads are not yet present, and during the actual measurement the current object signal Fig. 4 illustrates the method of the invention wherein the stored amplitude is subtracted from the amplitude, thereby outputting an output signal without crosstalk.

Claims (17)

  A magnetic sensor for detecting a leakage magnetic field generated by a magnetizable object when magnetized and generating an electric object signal dependent on the detected leakage magnetic field, wherein the sensor detects the magnetizable object A magnetic field generator for generating a main magnetic field for magnetizing, and for reducing the influence of a crosstalk signal component in the electric object signal caused by magnetic crosstalk between the main magnetic field and the leakage magnetic field Crosstalk reduction means, wherein the crosstalk reduction means is configured to distinguish signal characteristics between the crosstalk signal component and the rest of the electrical object signal and generate an electrical output signal. Sensor.   The sensor according to claim 1, wherein the signal characteristic is a phase of a signal.   The crosstalk reducing means includes means for generating an orthogonal electric signal orthogonal to the crosstalk signal component, and a multiplier for multiplying the orthogonal electric signal by the electric object signal. A sensor according to claim 2, characterized in that a later resulting signal forms a reference for the electrical output signal.   The crosstalk reducing means includes a low-pass filter that filters the resulting signal after the multiplication, and the resulting signal after the low-pass filter is the electrical output signal. Sensor.   The frequency of the main magnetic field is selected such that the phase difference expressed in radians between the detected leakage magnetic field and the main magnetic field is approximately equal to π / 2 + nπ, where n is an integer. The sensor according to claim 3 or 4, characterized in that.   The sensor according to claim 1, wherein the signal characteristic is a signal amplitude.   The main magnetic field has a first magnetic signal having a first frequency and a second frequency having a second frequency that is much longer than the first frequency and longer than the magnetization cutoff frequency of the magnetizable object. The first and second magnetic signals generate a first electrical signal component in the electrical object signal having the first frequency and a first amplitude, and the second magnetic signal. Generating a second electrical signal component in the electrical object signal having a frequency and a second amplitude, wherein the crosstalk reducing means measures the amplitude of the first and second electrical signal components and the measured 7. A sensor according to claim 6, comprising means for subtracting amplitudes from each other, the resulting signal after the subtraction forms a reference for the electrical output signal.   The crosstalk reducing means includes a low-pass filter for filtering the resultant signal after the subtraction, and the resultant signal after the low-pass filter is the electrical output signal. 8. The sensor according to 7.   The sensor according to claim 7 or 8, wherein the first frequency is lower than the magnetization cutoff frequency, and the second frequency is considerably higher than the magnetization cutoff frequency.   A magnetic sensor for detecting a leakage magnetic field generated by a magnetizable object when magnetized and generating an electric object signal dependent on the detected leakage magnetic field, wherein the sensor detects the magnetizable object A first external magnetic field generator for generating a first main magnetic field for magnetizing, and in the electric object signal caused by magnetic crosstalk between the first external main magnetic field and the leakage magnetic field Crosstalk reducing means for reducing the influence of a crosstalk signal component, and the crosstalk reducing means compensates for magnetic crosstalk between the first external main magnetic field and the leakage magnetic field. A sensor having a second external magnetic field generator for generating a second main magnetic field.   The first and second external magnetic field generators have first and second coils through which first and second alternating currents flow, respectively, and the first and second alternating currents have the same frequency. The magnetic sensor according to claim 10, wherein the magnetic sensor flows during operation of the magnetic sensor.   The crosstalk reducing means includes means for adapting a ratio between the amplitude of the first alternating current and the amplitude of the second alternating current in order to minimize the magnetic crosstalk. Item 12. The magnetic sensor according to Item 11.   The crosstalk reducing means includes means for adapting a difference between the phase of the first alternating current and the phase of the second alternating current in order to minimize the magnetic crosstalk. Item 13. The magnetic sensor according to Item 11 or 12.   A biochip comprising the magnetic sensor according to any one of claims 1 to 13. A method for detecting a leakage magnetic field generated by a magnetizable object when magnetized, comprising:
Generating a main magnetic field for magnetizing the magnetizable object;
Detecting a leakage magnetic field generated from the magnetizable object;
Generating an electrical object signal from the detected leakage magnetic field;
Distinguishing signal characteristics between a crosstalk signal in the electrical object signal caused by magnetic crosstalk between the main magnetic field and the detected leakage magnetic field, and the rest of the electrical object signal;
Utilizing the differentiated signal characteristics to generate an electrical output signal;
Having a method. A method for detecting a leakage magnetic field generated by a magnetizable object when magnetized, comprising:
Generating a first main magnetic field for magnetizing the magnetizable object;
Detecting a leakage magnetic field generated from the magnetizable object;
Generating an electrical object signal from the detected leakage magnetic field;
Generating a second main magnetic field to compensate for crosstalk signals in the electrical object signal caused by magnetic crosstalk between the first main magnetic field and the detected leakage magnetic field;
Generating an electrical output signal;
Having a method. A method for detecting a leakage magnetic field generated by a magnetizable object when magnetized, comprising:
In the first main step,
Generating a main magnetic field in the absence of a magnetizable object;
Detecting the magnetic field as if it were a stray field generated from the magnetizable object if there was a magnetizable object;
Generating an electrical object signal from the detected magnetic field;
Measuring the amplitude of the electrical object signal;
Storing the amplitude of the electrical object signal in a memory; and
In the second main step,
Generating a main magnetic field for magnetizing the magnetizable object;
Detecting a leakage magnetic field generated from the magnetizable object;
Generating a further electrical object signal from the detected leakage magnetic field;
Measuring the amplitude of the further electrical object signal;
Obtaining an amplitude of the stored electrical object signal;
Subtracting the stored amplitude and the amplitude of the further electrical object signal from each other, thereby generating an electrical output signal;
A step of performing
Having a method.

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